IBS is a functional disease of which main symptoms are evacuation abnormalities such as diarrhea or constipation and bellyache, and is not caused by intestinal organic lesion. This disease is developed as the result of mutual association of intestinal motion disorder, viscerosensory anaphylaxis and psychological and social factors.
Because 5-HT3 in intestine participates in intestinal contraction, secretion of intestinal juice, peristalsis and content transport, diarrheal symptoms can be improved by administration of 5-HT3 antagonist. In the United States, alosetron which is a 5-HT3 antagonist has been approved as an IBS treating agent. Also other 5-HT3 antagonists, for example, ondansetron, alosetron, tropisetron, granisetron and so on are disclosed in WO 99/17755 Pamphlet and U.S. Pat. No. 6,284,770, which publications disclose that 5-HT3 antagonistic medicines are useful for IBS treating agent.
On the other hand, because psychological and social factors are recognized to be one of the origins of IBS, administration of benzodiazepine antianxiety agent in IBS therapy has been experimented. Recently, novel serotonin agonistic antianxiety agent, for example, non-benzodiazepine compounds showing less adverse effect are under development and of which application for IBS therapy is expected.
J. Med. Chem., 40, 574-585 (1997) and Eur. J. Med. Chem., 35, 677-689 (2000) disclose pyrimidinone derivatives having selective affinity to 5-HT1A. In these literature references, the derivatives' selectivity for 5-HT1A over α1 receptor was investigated. Also EP 343,050, WO 01/32659 Pamphlet, JP 2001-97978A and J. Med. Chem., 32, 1147-1156 (1989) disclose piperazinyl isoquinoline derivatives, piperazinyl thienopyridine derivatives and piperazinyl furopylidine derivatives which exhibit affinity to 5-HT1A and the like. While these references describe psychic action based on 5-HT1A agonistic activity, they are silent on 5-HT3. They contain no disclosure or suggestion on the named derivatives' application to IBS or associated diseases based on their activities on the two receptors.
J. Med. Chem., 42, 4362-4379 (1999) discloses piperazinyl-pyrazine derivatives having selective affinity to 5-HT3, but their action is agonistic.
In Japan, tandospirone which is a 5-HT1A agonist is marketed, of which indication is stress-caused dyspeptic ulcer. This indication is attributable to removal of stress by the antianxiety action of tandospirone, and IBS is not included in its indications.
As above, currently many 5-HT3 antagonists and 5-HT1A agonists are developed or marketed, but all of these 5-HT3 antagonists and 5-HT1A agonists have unilateral activities. Because IBS has plural origins, therapeutic effect of these compounds on IBS is insufficient.
Only recently, Bioorg. Med. Chem. Lett., 13, 3177-3180 (2003) disclosed compounds which exhibit affinity to both of the receptors 5-HT3 and 5-HT1A. These compounds, however, are benzimidazole-arypiperazine derivatives, and the literature refers only to the compounds' action on nervous system, containing no disclosure or suggestion on combination of 5-HT3 antagonistic activity and 5-HT1A agonistic activity on IBS or the effect based on the combination.
We have engaged in concentrative studies to discover simultaneous expression in vivo of 5-HT3 antagonistic activity and 5-HT1A agonistic activity is very effective for treating the diseases associated with both hyperactivity or expression enhancement of 5-HT3 and hypoactivity of 5-HT1A, in particular, treating IBS.